Impaired tissue healing is a significant problem in health care. Chronic, non-healing wounds are a major cause of prolonged morbidity in the aged human population. Tissue repair is particularly relevant to bedridden or diabetic patients who develop severe, external, non-healing skin ulcers. In addition, those patients suffering from internal lesions, such as those associated with disorders of the digestive tract, are particularly susceptible to the effects of non or slow-healing tissue damage.
Pharmaceutical agents that promote tissue regeneration at the site of a lesion, such as growth factors, have been utilized to accelerate wound repair. Growth factors are molecules that function not only as growth simulators (mitogens), but also as growth inhibitors. Growth factors are also known to stimulate cell migration (e.g., mitogenic cytokines), function as chemotactic agents, inhibit cell migration or invasion of tumor cells, modulate differentiated functions of cells, be involved in apoptosis, and promote survival of cells. For example, epidermal growth factor (EGF) is a mitogen that not only effects suppression of gastric acid secretion and fetal lung development, but also effects wound healing and epidermal regeneration (Franklin et al., J. Lab. Clin. Med., 108:103, 1985). EGF has been shown to be a potent stimulator of epithelial cell proliferation in the human intestine (Alison et al., Cell Biol. Int., 18:1, 1994) and other tissues.
Previous studies have demonstrated the viability of targeting extracellular matrix molecules, such as exposed collagen, for delivery of a pharmaceutical agent to a specific tissue. For example, von Willebrand Factor (vWF)-derived collagen-binding domains have been used to target the TGF-β family of growth factors to damaged tissue (Tuan et al., Conn. Tiss. Res., 34:1, 1996; Han et al., Protein Expr. Purif., 11:169, 1997).
Pharmaceutical agents that promote tissue regeneration are useful not only for treating disorders associated with impaired tissue regeneration, but also for promoting tissue regeneration associated with surgical procedures, for example. Several strategies have been developed to accomplish enhanced tissue repair for the treatment of damaged tissue. Within these strategies, there is a need for the controlled, sustained, site-specific targeting of a pharmaceutical agent to a wound site for the purpose of promoting tissue regeneration.